Method for the production of small spherical particles containing at least one water-insoluble linear polysaccharide

ABSTRACT

The present invention relates to a method for the production of small spherical particles consisting totally or partly of at least one water-insoluble linear polysaccharide by dissolving the at least one water-insoluble polysaccharide in a solvent or a solvent mixture, introducing the solution into a precipitating agent or a precipitating agent mixture, optionally cooling the mixture thus obtained and separating the formed small particles, wherein at least one poly alpha D-glucan soluble in hot water is used as auxiliary agent for precipitation. The invention also relates to the particles obtained according to said method.

This is the U.S. national phase of International Application No.PCT/EP99/05975 filed Aug. 14, 1999, the entire disclosure of which isincorporated herein by reference.

The present invention relates to a method for preparing small sphericalparticles which consist entirely or partly of at least onewater-insoluble linear polysaccharide and also to particles obtainableby this method.

The applicant's German patent application No. 19737481.6 which hasearlier priority but is not a prior publication describes methods forpreparing spherical microparticles containing water-insoluble linearpolysaccharides. This method can produce spherical microparticles whichstand out in particular due to high uniformity with respect to theirshape and their diameter distribution and also due to good mechanicalproperties. Owing to their comparatively uniform constitution and withsimultaneously good mechanical properties, these particles may beemployed for a multiplicity of applications.

It has, however, become apparent that, depending on the intendedapplication, a specific optimization of particular particle propertiesmay be desirable.

The abovementioned method can in particular produce particles with anaverage diameter of generally 1 μm or greater. There has been a needtherefore to develop an optimized method which may be used forspecifically preparing small particles whose average diameter does notexceed a few micrometers and is in particular in the nanometer range.

It was therefore an object of the present invention to provide a methodwhich can be used for reproducibly producing in a simple mannerwater-insoluble spherical particles which contain linear polysaccharidesand which have, aside from a regular shape, uniform diameterdistribution and also good mechanical properties, a particularly smallaverage diameter which does not exceed a few micrometers and which ispreferably in the nanometer range.

This object is achieved by a method for preparing small sphericalparticles which consist entirely or partly of at least onewater-insoluble linear polysaccharide by dissolving the at least onewater-insoluble linear polysaccharide in a solvent or solvent mixture,introducing the solution formed into a precipitant or precipitantmixture, where appropriate cooling the mixture being produced in theprocess and removing the particles formed, wherein at least onehot-water-soluble poly-alpha-D-glucan is used as a precipitation aid.

The present invention further relates to small spherical particles asobtainable according to the abovementioned method.

In this respect, the present invention means an advantageous inventivedevelopment of the abovementioned German patent application No.19737481.6 whose contents are incorporated in their entirety by way ofreference for the purposes of the present invention.

Although said application also discusses the use of precipitation aids,there is no information on the use of hot-water-solublepoly-alpha-D-glucan, in particular no information on using suchcompounds in order to specifically control the size of the particles.

FIGS. 1 to 8 show scanning electron micrographs (SEM, Camscan S-4) ofspherical particles:

FIG. 1: particles of the invention according to Example 1, magnification5000×,

FIG. 2: particles as in FIG. 1, magnification 20 000×,

FIG. 3: particles of the invention according to Example 2, magnification5000×,

FIG. 4: particles of the invention according to FIG. 3, magnification 20000×,

FIG. 5: particles according to Comparative Example 1, magnification5000×,

FIG. 6: particles according to FIG. 5, magnification 20 000×,

FIG. 7: particles according to Comparative Example 3, magnification5000×, and

FIG. 8: particles according to FIG. 7, magnification 20 000×.

Linear water-insoluble polysaccharides in accordance with the presentinvention are polysaccharides composed of monosaccharides, disaccharidesor other monomeric components such that the individual components arealways linked to each other in the same way. Each base unit or componentdefined in this way has exactly two linkages, each one to anothermonomer. The only exceptions are the two base units forming the startand the end of the polysaccharide which have only one linkage to anothermonomer.

Examples of preferred water-insoluble linear polysaccharides are linearpoly-D-glucans in which the type of linkage is unimportant, as long aslinearity in accordance with the invention is present. Examples arepoly(1,4-alpha-D-glucan) and poly(1,3-beta-D-glucan),poly(1,4-alpha-D-glucan) being particularly preferred.

If the base unit has three or more linkages, then this is referred to asbranching. The number of hydroxyl groups per 100 base units, which arenot involved in constructing the linear polymer backbone and which formbranchings, constitutes the so-called degree of branching.

According to the invention, the linear water-insoluble polysaccharideshave a degree of branching of less than 8%, i.e. less than 8 branchingsper 100 base units. The degree of branching is preferably less than 4%and in particular not more than 1.5%.

If the water-insoluble linear polysaccharide is a polyglucan, forexample poly(1,4-alpha-D-glucan), then the degree of branching atposition 6 is less than 4%, preferably not more than 2% and inparticular not more than 0.5%, and the degree of branching at the otherpositions, for example at positions 2 and 3, is preferably not more than2% and in particular not more than 1%.

Particular preference is given to polysaccharides, in particularpoly-alpha-D-glucans, which have no branchings or whose degree ofbranching is so minimal as to be undetectable by conventional methods.

According to the invention, the prefixes “alpha”, “beta” or “D” refersolely to the linkages forming the polymer backbone and not to thebranchings.

For the present invention, the term “water-insoluble polysaccharides”means compounds which according to the definition of the DeutschesArzneimittelbuch [German Pharmacopeia] (DAB—Deutsches Arzneimittelbuch,Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, Govi-Verlag GmbH,Frankfurt, 9th edition, 1987) are classified as “sparingly soluble”,“slightly soluble”, “very slightly soluble” and “practically insoluble”,corresponding to classes 4 to 7.

For the present invention, preference is given to from slightly solubleto practically insoluble compounds, in particular to from very slightlysoluble to practically insoluble compounds.

In the case of the polysaccharides used according to the invention, thismeans that preferably at least 98% of the amount employed, in particularat least 99.5%, are insoluble in water (corresponding to classes 4 and5, respectively) under standard conditions (T=25° C.+/−20%, p=101 325Pascal+/−20%).

The following protocol may illustrate “very slightly soluble”,corresponding to class 6:

One gram of the polyglucan/polysaccharide to be studied is heated to130° C. in 1 l of deionized water at a pressure of 1 bar. The solutionforming remains stable only briefly for a few minutes. During coolingunder standard conditions, the substance precipitates again. Aftercooling to room temperature and separation by means of centrifugation,at least 66% of the amount employed can be recovered, taking intoaccount experimental losses.

The polysaccharides employed according to the invention may be of anyorigin, as long as the abovementioned conditions with respect to theterms “linear” and “water-insoluble” are met.

They may have been obtained naturally or via biotechnology.

They may be produced, for example, from natural plant or animal sourcesby isolation and/or purification.

It is also possible to use sources which have been geneticallymanipulated such that they contain a higher proportion of unbranched orcomparatively slightly branched polysaccharides than the unmanipulatedsource.

They may have been prepared from non-linear polysaccharides by enzymaticor chemical debranching.

Biotechnological methods comprise biocatalytic, also biotransformation,or fermentation processes.

WO 95/31553, for example, describes an advantageous method for thebiotechnological production.

Modified water-insoluble linear polysaccharides may also be used, itbeing possible for the polysaccharides to have been chemically modified,for example by esterification and/or etherification at one or more ofthe positions not involved in the linear linkage. In the case of thepreferred 1,4-linked polyglucans, modification may take place atpositions 2, 3 and/or 6. Measures for such modifications are well knownto the skilled worker.

Thus linear polysaccharides such as pullulans, pectins, mannans orpolyfructans, which are water-soluble or swellable per se, can be madewater-insoluble through modification.

It is further possible to use so-called alpha-amylase-resistantpolysaccharides as described, for example, in the German patentapplication No. 198 30 618.0.

Further suitable examples for water-insoluble linear polysaccharides andalso a detailed explanation with respect to the preparation methodsthereof are to be found in the German applications of the sameapplicant, Nos. 197 37 481.6, 198 03 415.6, 198 16 070.4, 198 30 618.0and 198 27 978.7 which have earlier priority but are not priorpublications and which are explicitly referred to here.

The molecular weights M_(W) (weight average, determined by means of gelpermeation chromatography and comparison with a calibration using apullulan standard) of the linear polysaccharides used according to theinvention may vary within a wide range from 10³ g/mol to 10⁷ g/mol. Themolecular weight M_(w) preferably is in the range from 10⁴ g/mol to 10⁵g/mol and particularly preferably from 2×10⁴ g/mol to 5×10⁴ g/mol.Another advantageous range is from 2×10³ g/mol to 8×10³ g/mol.Corresponding ranges apply to the preferably used poly-D-glucan andpoly(1,4-a-D-glucan).

The molecular weight distribution or polydispersity M_(W)/M_(N) maylikewise vary widely, depending on the polysaccharide preparationmethod. Preferred ranges are from 1.01 to 50, and in particular from 1.5to 15. Polydispersity increases with a bimodal molecular weightdistribution.

For the method of the invention, a single linear polysaccharidesubstance, in particular linear poly-D-glucan, preferablypoly(1,4-a-D-glucan), or mixtures of two or more representatives may beused.

The hot-water-soluble poly-alpha-D-glucans used as precipitation aidsaccording to the invention are likewise polysaccharides. In contrast towater-insoluble linear polysaccharides, they may contain branchings andform no alpha-amylase-resistant polysaccharides having aresistant-starch content (RS content) of 65% or greater.

Like the water-insoluble linear polysaccharides used as startingmaterials, they may be of any origin. They may have been obtained fromnatural sources such as, for example, plants or animals, throughtechnical or biotechnological methods, for example through biocatalysisor fermentation.

The poly-alpha-D-glucans used according to the invention may be obtainedfrom genetically or biotechnologically modified plants.

The genetic or biotechnological modification may lead, for example, tothe production of a polyglucan having a relatively large linearproportion or to a relatively easy separation of the containingpolyglucans.

They may have been modified at those positions not involved in linkages,for example by etherification, esterification or oxidation or by othersuitable methods.

It is also possible to use degradation products of relatively largepolymer molecules.

The poly-alpha-D-glucans may be subjected to further processing methods,for example purification methods for isolating unwanted by-products orincreasing the linear structures.

Using debranching techniques may also increase the linear structures, asdescribed, for example, for the water-insoluble linear polysaccharides.

It goes without saying that all production measures suitable forwater-insoluble linear polysaccharides can likewise be applied tohot-water-soluble poly-alpha-D-glucans.

Preferred representatives of the hot-water-soluble poly-alpha-D-glucansused for the method of the invention are native or chemically modifiedstarches, poly-alpha-D-glucans obtained from said starches, and alsostarch-like compounds.

A group of starches which may be used within the framework of theinvention comprises starches obtained from plant raw material. Theseinclude inter alia starches from tubers such as potatoes, cassavas,arrowroots, yams, from seeds such as wheat, maize, rye, rice, barley,millet, oat, sorghum, from fruits such as chestnuts, acorns, beans, peasand similar pulses, bananas, and also from pith, for example of the sagopalm.

The starches obtainable from plant raw material usually and essentiallycomprise amylose, a poly(1,4-alpha-D-glucan), and amylopectin, apoly(1,4-alpha-D-glucan) with 1,6 branchings, in variable quantitativeratios.

For example, starch from potatoes contains approx. 20% by weight ofamylose and approx. 80% by weight of amylopectin, while starch frommaize contains approx. 50% by weight of amylose and approx. 50% byweight of amylopectin.

Starch-like compounds mean compounds which comprise poly-alpha-D-glucansbut which are not from plants. Examples are glycogen, apoly-alpha-D-glucan which corresponds to amylopectin and which is ofanimal origin, and dextran which is obtained from bacteria.

The hot-water-soluble poly-alpha-D-glucans may be employed as a mixtureof a linear and a branched proportion, as in starch, for example. Inthis case, the proportion of linear poly-alpha-D-glucan should begreater than 15% by weight, preferably 50 to 99.5% by weight, inparticular 60 to 90% by weight and very particularly preferably 65 to80% by weight, with respect to the total amount of poly-alpha-D-glucanin the precipitant.

They may, however, also comprise branched structures, as in amylopectinor in glycogen, for example. A branched structure is present if thedegree of branching is greater than indicated above for the linearpolysaccharides.

In the context of the present invention, “hot-water-soluble” means thatthe poly-alpha-D-glucans are essentially insoluble at room temperature,with the same standard being applied as for the term “water-insoluble”in connection with linear polysaccharides. The term “solution” or“solubility” means in particular also suspensions or formation ofsuspensions like those appearing when dissolving starch.

For example, the hot-water-soluble starches preferred according to theinvention have negligible solubility in water at room temperature, whilethe so-called cold-water-soluble starches are more freely soluble underthese conditions.

Hot-water-soluble starches are characterized in particular by formingsolutions when heated under autogenous pressure, for example in anautoclave, to a temperature in the range from about 100 to about 160°C., the particular temperature depending on the type of starch.

It is, for example, possible to dissolve potato starch completely atabout 100° C., while maize starch requires appr. 125° C.

For the method of the invention, the hot-water-solublepoly-alpha-D-glucans are preferably added at maximum concentration tothe precipitant, i.e. a saturated solution is prepared.

Further suitable ranges are from greater than 0.001% by weight to 10% byweight, preferably from 0.01 to 2% by weight, and in particular from0.05% by weight to 0.5% by weight, with respect to the amount ofprecipitant used.

According to a further embodiment, the linear water-insolublepolysaccharide(s) may also be admixed with other polymers, in particularother biocompatible or biodegradable polymers. The amount of the otherpolymer(s) which is (are) admixed without changing the spherical shapeand/or other properties of the particles to be prepared, always dependson the polymer added. The amount may be up to 10% or more, with respectto the total amount of water-insoluble polysaccharide employed, i.e.linear or, where appropriate, branched (as indicated in the following),and also less in particular cases. The maximum amount allowed depends onthe particular individual case and can be readily determined by askilled worker through standard experiments.

The further polymer may be a water-insoluble branched polysaccharide,preferably a polyglucan, in particular a poly(1,4-alpha-D-glucan) or apoly(1,3-beta-D-glucan). The water-insoluble branched polysaccharide mayalso be a hot-water-soluble poly-alpha-D-glucan as can be employed asprecipitation aid according to the invention.

In this context, the degree of branching is negligible. The proportionof branched polysaccharide, however, should not exceed 30% by weight,preferably 20% by weight and in particular 10% by weight, with respectto the total amount of water-insoluble polysaccharide.

It is also possible to add mixtures of two or more branchedpolysaccharides.

The branched polysaccharides may be of any origin. In this connection,the explanations on this matter for the linear polysaccharides arereferred to. Preferred sources are starch and starch analogs such asglycogen. If required, suitable concentration methods may increase theproportion of linear structures in the branched polysaccharides.

Regarding water-insolubility and essentially also molecular weight, thesame information applies as for the linear polysaccharide, but themolecular weight of the branched polysaccharides may be higher thanindicated for the water-insoluble linear polysaccharides.

Examples of precipitants are water, dichloromethane, a mixture of waterand dichloromethane, mixtures of water and alcohols such as methanol,ethanol, isopropanol, with water and also a mixture of water anddichloromethane being particularly preferred.

To prepare the particles of the invention, the starting materials suchas the at least one linear polysaccharide and, where appropriate,further polymers, etc. are dissolved in a solvent. Examples of suitablesolvents are dimethyl sulfoxide (DMSO), formamide, acetamide,N,N-dimethylformamide, N,N-di-methylacetamide, N-methylmorpholineN-oxide in the presence of water, further N-substituted morpholineN-oxides, aqueous solutions with high or low pH, or mixtures of theabovementioned solvents, DMSO being particularly preferred. It is alsopossible, of course, to use other solvents familiar to the skilledworker for this purpose.

The total concentration of linear polysaccharide in the solvent may varywithin wide limits according to demand. It is preferably in a range from0.02 g (linear polysaccharide)/ml (solvent) to 1.0 g/ml, in particularfrom 0.05 g/ml to 0.8 g/ml and particularly preferably from 0.3 g/l to0.6 g/l.

The solvent/precipitant ratio is preferably in a range from 1:1000 to1:4 (part of solvent/parts of precipitant) preferably 1:100 to 1:10 andin particular 1:70 to 1:30.

According to a preferred embodiment, the solution containing thestarting materials is combined with the precipitant at from 20° C. to50° C.

If mixing takes place at an elevated temperature, then the mixture beingproduced may subsequently be cooled, if required.

The order in which solvent and precipitant are combined, for examplewhether the precipitant is added to the solvent or vice versa, isunimportant. It is, however, important to ensure rapid mixing.

The temperature during the precipitation process is generally maintainedat from plus 10° C. to minus 10° C., preferably plus 5° C. and minus 5°C. A higher or lower temperature may be chosen, if required.

The precipitation process may be carried out relatively slowly at lowtemperature overnight. It can be influenced and controlled by varyingthe temperature and the precipitant. If the mixture of solvent andprecipitant is cooled, it must be ensured that said mixture stays liquidand does not solidify.

Furthermore, addition of other precipitation aids may affect processcontrol and also particle properties such as size etc.

Examples of suitable precipitation aids which may be employed aside fromthe hot-water-soluble poly-alpha-D-glucan are surfactants such as sodiumdodecyl sulfate, N-methylgluconamide, polysorbates (e.g. Tween(trademark)), alkyl polyglycol ethers, ethylene oxide/propylene oxidecopolymers (e.g. Pluronic (trademark)), alkyl polyglycol ether sulfates,generally alkyl sulfates and glycol fatty esters, sugars such as, forexample, fructose, sucrose, glucose and water-soluble cellulosederivatives.

The surfactants may be anionic, cationic or nonionic.

It is possible to produce particularly regular, i.e. smooth, surfaces byadding water-soluble cellulose derivatives. It is in principle possibleto use any water-soluble cellulose derivative, as long as it is suitableas a precipitation aid. The celluloses in this case may be chemicallymodified celluloses of any kind. Examples are cellulose esters andcellulose ethers and mixed forms thereof. Specific representatives are,for example, hydroxypropylmethyl-celluloses, hydroxyethylcelluloses,carboxymethyl-celluloses, cellulose acetates, cellulose butyrates,cellulose propionates, cellulose acetobutyrates, celluloseacetopropionates, cellulose nitrates, ethyl-celluloses,benzylcelluloses, methylcelluloses etc.

Mixtures of different water-soluble cellulose derivatives may also beemployed.

For the present invention, the term “water-soluble cellulosederivatives” means compounds classified as very soluble to slightlysoluble according to the definition of the Deutsches Arzneimittelbuch[German Pharmacopeia] (DAB=Deutsches Arzneimittelbuch, WissenschaftlicheVerlagsgesellschaft mbH, Stuttgart, Govi-Verlag GmbH, Frankfurt, 9thedition, 1987).

Usually, these other aids are likewise added to the precipitant. Theamount used depends on the particular individual case and also on thedesired particle properties, and the skilled worker is familiar withdetermining the advantageous amount for each case.

Concentrations proven to be advantageous are from 2 g (aid)/l(precipitant) to 150 g/l, and preferably from 5 g/l to 80 g/l and inparticular 80 g/l to 20 g/l. These values in particular apply also tothe water-soluble cellulose derivative.

The spherical particles which are obtainable according to the method ofthe invention and which this invention likewise relates to, have auniform spherical shape, narrow size distribution and good mechanicalproperties, like the microparticles described in the German patentapplication No. 19737481.6. In addition, using the hot-water-solublepoly-alpha-D-glucans as precipitation aids makes it possible to optimizethe method in the direction of small particles and preferably into thenanometer range.

Thus, the particles of the invention generally have average diameters(dn, number average) of from 100 nm to 2 μm, preferably 250 nm to 1.3 μmand particularly preferably 500 nm to 1.0 μm.

Spherical in accordance with the invention means that the particles havenearly a spherical shape. If a sphere is described by axes of identicallength which start from a common origin, are directed into space anddefine the radius of the sphere in all spatial orientations, the lengthof the axes may deviate from an ideal spherical state by from 1% to 40%for the spherical particles. Preferably, spherical particles withdeviations of up to 25% are obtained, particularly preferably up to 15%.

The surface of the spherical particles can be macroscopically comparedto a raspberry, with the depth of the irregularities on the particlesurface, such as recesses or indentations, being not more than 20% ofthe average diameter of the spherical microparticles.

Furthermore, the particles of the invention preferably show a dispersityD=weight average diameter(d_(w))/number average diameter(d_(n)) of from1.0 to 10.0, preferably from 1.5 to 5.0 and in particular from 2.0 to3.0.

The averages used herein are defined as follows:

d_(n) = n_(i) × d_(i)/n_(i) = number average d_(w) = n_(i) × d_(i)²/n_(i) × d_(i) = weight average n_(i) = number of particles withdiameter d_(i), d_(i) = a particular diameter, i = serial parameter.

The term weight in this connection represents a weighted average. Thelarger diameters are given greater importance.

It goes without saying that the particles obtainable by the method ofthe invention are suitable for all applications as listed in the Germanpatent applications Nos. 19737481.6, 19803415.6, 19816070.4 or19816085.2 which have earlier priority but are not prior publications.

Thus, they can be employed in pure form or as vehicles for activesubstances in the widest sense, for example

as additives for cosmetics in ointments, dusting powders, creams, pastesetc.,

as vehicles for active substances in pharmaceutical, animal experimentaland other similar applications,

as smoothing agents, for example for closing pores or smoothing flashes,

as food additive, for example as bulking component or for improvingrheological properties,

as additive for upgrading, for example, emulsion polymers,

as separation aids, for example in the removal of impurities,

as encapsulating material,

as vehicles for magnetic particles etc.,

as filler, in particular for biodegradable polymers or industrialpolymers, for example for controlling properties,

as additive for controlling properties, for example the porosity, theweight, the color etc.,

as particle standard for calibration or determination of the particlesize of unknown materials etc.,

as vehicle material for the controlled, e.g. slow, release of activesubstances,

as bulking agent for improving the properties of industrial orbiocompatible polymers,

in diagnostic tests, for example as ultrasound agent.

Owing to their natural origin, most of the water-insoluble linearpolysaccharides used according to the invention and of the degradationproducts thereof, in particular polyglucans such aspoly(1,4-alpha-D-glucan), are biocompatible and biodegradable. They arewell tolerated in tissues and do not accumulate in the animal, inparticular human, body. Biodegradation means in this context any in vivoprocess leading to degradation or destruction of substances, in thiscase polysaccharides.

These properties of biocompatibility and biodegradability areparticularly advantageous for uses concerning human or animal organisms,for example in medicine, pharmacy or cosmetics.

The following examples explain the invention in more detail. Theseexamples are for illustration purposes and are not limiting.

EXAMPLES 1, 2 Comparative Example 1 a. Preparation of the PrecipitationSolution

100 ml of deionized water were added to in each case 100 mg of thehot-water-soluble starches listed in Table 1. The suspension obtainedwas heated to approx. 90° C. with stirring until a 0.1% strength aqueoussolution was obtained.

b. Preparation of the Particles

1.0 g of poly(1,4-alpha-D-glucan) was in each case dissolved in 5 ml ofdimethyl sulfoxide (DMSO, analytical grade, from Riedel-de-Haen) at 60°C. The DMSO solutions were added dropwise and with stirring to in eachcase 100 ml of the precipitant prepared under a. within a few seconds.The mixtures obtained were stored at 5° C. for 16 hours. In each case, afine white precipitate of particles developed in the form of a milkysuspension. The particles were removed by homogeneously suspending eachmixture and subsequent centrifugation at 3000 revolutions per minute forabout 15 minutes (Labofuge GL from Herarus). The solid residue of eachmixture was resuspended in double-distilled water three times in totaland again centrifuged. The solid obtained in this process wasresuspended in approx. 10 ml of double-distilled water, frozen andlyophilized (Christ Delta 1-24 KD freeze-dryer).

The results are listed in the following Table 1.

TABLE 1 Amylose Yield Type of starch content (%) (%) Example 1 Maize 7073 Hylon VII* Example 2 Maize 20 80 Starch* Comparative Amioca <1 64Example 1 powder* *each from National Starch Chemistry

Characterization of the spherical particles obtained in Examples 1 and 2and in Comparative Example 1 was carried out by means of scanningelectron micrographs (SEM; Camscan S-4), see FIGS. 1 to 6.

The results are listed in Table 2.

TABLE 2 Comparative Example 1 Example 2 example 1 Size 0.5 μm 0.5-1.0 μm1.0-2.0 μm Shape spherical Spherical irregular Surface smooth, Smooth,Rough, characteristics i.e. < 20% i.e. < 20% i.e. > 20% (max. depth) dndn dn Particle unique unique partly fused

Comparative Examples 2 and 3

Preparation of particles without addition of starch to the precipitantand with addition of cold-water soluble starches

The preparation was carried out essentially as in Examples 1 and 2. Thestarch concentration in the precipitant was 0.1% in each case.

The results listed in Table 3 clearly show the effect of starch asprecipitation aid with respect to particle size and shape.

TABLE 3 Comparative Comparative Example 2 Example 1 example 3 Starchwithout q.v. Crisp Film* Size 1.0-2.0 μm 0.5 μm >2.0 μm Shape SphericalSpherical spherical Surface Smooth, Smooth, Rough, characteristics i.e.< 20% i.e. < 20% i.e. > 20% (max. depth) d_(n) d_(n) d_(n) ParticleUnique unique Partly fused *cold-water soluble starch from NationalStarch Chemistry (amylose content: approx. 50%).

What is claimed is:
 1. A method for preparing spherical particlescomprising at least one water-insoluble linear polysaccharide, saidmethod comprising the steps of (a) dissolving the at least onewater-insoluble linear polysaccharide in a solvent or solvent mixture toform a solution, (b) introducing the solution into a precipitant orprecipitant mixture to form a polysaccharide-precipitant mixturecontaining polysaccharide particles, and where appropriate cooling thepolysaccharide-precipitant mixture, and (c) removing the particlesformed, wherein at least one hot-water-soluble poly-alpha-D-glucan isused as a precipitation aid.
 2. The method as claimed in claim 1,wherein the hot-water-soluble poly-alpha-D-glucan is derived from anatural source.
 3. The method as claimed in claim 2, wherein the naturalsource is a plant or an animal.
 4. The method as claimed in claim 1,wherein the poly-alpha-D-glucan is a native starch.
 5. The method asclaimed in claim 1, wherein the poly-alpha-D-glucan is glycogen.
 6. Themethod as claimed in claim 1, comprising chemically modifying thepoly-alpha-D-glucan prior to forming said mixture.
 7. The method asclaimed in claim 1, wherein the hot-water-soluble poly-alpha-D-glucan isa mixture of a linear polyglucan and a branched polyglucan.
 8. Themethod as claimed in claim 7, wherein the content of the linearpoly-alpha-D-glucan in the poly-alpha-D-glucan mixture is greater than15% by weight relative to the total weight of poly-alpha-D-glucan. 9.The method as claimed in claim 8, wherein the content of the linearpoly-alpha-D-glucan in the poly-alpha-D-glucan mixture is between 50%and 99.5% by weight relative to total weight.
 10. The method as claimedin claim 1, wherein the hot-water-soluble poly-alpha-D-glucan is presentin the precipitant in the form of a saturated solution.
 11. The methodas claimed in claim 1, which comprises the steps of mixing the solutionand the precipitant at from 20 to 50° C. and cooling the mixture beingproduced to from plus 10° C. to minus 10° C.
 12. The method as claimedin claim 10, which comprises the step of cooling thepolysaccharide-precipitant mixture to a temperature in the range of plus5° C. to minus 5° C.
 13. The method as claimed in claim 1, wherein theprecipitant comprises water.
 14. The method as claimed in claim 1,wherein the solvent is dimethyl sulfoxide.
 15. The method as claimed inclaim 1, wherein the water-insoluble linear polysaccharide is a linearpolyglucan.
 16. The method as claimed in claim 1, wherein thewater-soluable linear polysaccharide is poly(1,4-alpha-D-glucan). 17.The method as claimed in claim 1, wherein the water-insoluble linearpolysaccharide is poly(1,3-beta-D-glucan).
 18. The method as claimed inclaim 1, comprising chemically modified the water-insoluble linearpolysaccharide prior to forming said mixture.
 19. The method as claimedin claim 18, wherein the polysaccharide has been esterified and/oretherified at at least one of the positions not involved in forming thepolymer chain.
 20. The method as claimed in claim 19, wherein thepolysaccharide has been esterified and/or etherfied at at least one ofpositions 2, 3 and 6.